Brief Report: HIV-1 Infection Impairs CD16 and CD35 Mediated Opsonophagocytosis of Mycobacterium tuberculosis by Human Neutrophils.
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ABSTRACT:
SUBMITTER: Bangani N
PROVIDER: S-EPMC5018214 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The bacterial pathogen Staphylococcus aureus responds to the host environment by increasing the thickness of its cell wall. However, the impact of cell wall thickening on susceptibility to host defenses is unclear. Using bacteria incubated in human serum, we show that host-induced increases in cell wall thickness led to a reduction in the exposure of bound antibody and complement and a corresponding reduction in phagocytosis and killing by neutrophils. The exposure of opsonins bound to protein antigens or lipoteichoic acid (LTA) was most significantly reduced, while opsonization by IgG against wall teichoic acid or peptidoglycan was largely unaffected. Partial digestion of accumulated cell wall using the enzyme lysostaphin restored opsonin exposure and promoted phagocytosis and killing. Concordantly, the antibiotic fosfomycin inhibited cell wall remodeling and maintained the full susceptibility of S. aureus to opsonophagocytic killing by neutrophils. These findings reveal that host-induced changes to the S. aureus cell wall reduce the ability of the immune system to detect and kill this pathogen through reduced exposure of protein- and LTA-bound opsonins.ImportanceUnderstanding how bacteria adapt to the host environment is critical in determining fundamental mechanisms of immune evasion, pathogenesis, and the identification of targets for new therapeutic approaches. Previous work demonstrated that Staphylococcus aureus remodels its cell envelope in response to host factors and we hypothesized that this may affect recognition by antibodies and thus killing by immune cells. As expected, incubation of S. aureus in human serum resulted in rapid binding of antibodies. However, as bacteria adapted to the serum, the increase in cell wall thickness resulted in a significant reduction in exposure of bound antibodies. This reduced antibody exposure, in turn, led to reduced killing by human neutrophils. Importantly, while antibodies bound to some cell surface structures became obscured, this was not the case for those bound to wall teichoic acid, which may have important implications for vaccine design.
| S-EPMC11323798 | biostudies-literature
Project description:The human respiratory tract pathogen Chlamydia pneumoniae, which causes mild to severe infections, has been associated with the development of chronic inflammatory diseases. To understand the biology of C. pneumoniae infections, several studies have investigated the interaction between C. pneumoniae and professional phagocytes. However, these studies have been conducted under nonopsonizing conditions, making the role of opsonization in C. pneumoniae infections elusive. Thus, we analyzed complement and antibody opsonization of C. pneumoniae and evaluated how opsonization affects chlamydial infectivity and phagocytosis in human monocytes and neutrophils. We demonstrated that IgG antibodies and activation products of complement C3 and C4 are deposited on the surface of C. pneumoniae elementary bodies when incubated in human serum. Complement activation limits C. pneumoniae infectivity in vitro and has the potential to induce bacterial lysis by the formation of the membrane attack complex. Coculture of C. pneumoniae and freshly isolated human leukocytes showed that complement opsonization is superior to IgG opsonization for efficient opsonophagocytosis of C. pneumoniae in monocytes and neutrophils. Neutrophil-mediated phagocytosis of C. pneumoniae was crucially dependent on opsonization, while monocytes retained minor phagocytic potential under nonopsonizing conditions. Complement opsonization significantly enhanced the intracellular neutralization of C. pneumoniae in peripheral blood mononuclear cells and neutrophils and almost abrogated the infectious potential of C. pneumoniae In conclusion, we demonstrated that complements limit C. pneumoniae infection in vitro by interfering with C. pneumoniae entry into permissive cells by direct complement-induced lysis and by tagging bacteria for efficient phagocytosis in both monocytes and neutrophils.
| S-EPMC7309617 | biostudies-literature
Project description:Nontuberculous mycobacteria (NTM), including Mycobacterium avium, are clinically important pathogens in cystic fibrosis (CF). The innate immune response to M. avium remains incompletely understood. We evaluated the role of complement opsonization in neutrophil-mediated killing of M. avium. Killing assays were performed using neutrophils from healthy donors (HDs) and persons with CF (pwCF). Clinical isolates of M. avium were opsonized with plasma from HDs or pwCF, which was intact or heat-treated to inactivate complement. HD neutrophils had killing activity against M. avium opsonized with intact HD plasma and killing was significantly reduced when M. avium was opsonized with heat-inactivated HD plasma. When opsonized with HD plasma, CF neutrophils had killing activity against M. avium that was not different than HD neutrophils. When opsonized with intact plasma from pwCF, HD neutrophil killing of M. avium was significantly reduced. Opsonization of M. avium with C3-depleted serum or IgM-depleted plasma resulted in significantly reduced killing. Plasma C3 levels were elevated in pwCF with NTM infection compared to pwCF without NTM infection. These studies demonstrate that human neutrophils efficiently kill M. avium when opsonized in the presence of plasma factors from HD that include C3 and IgM. Killing efficiency is significantly lower when the bacteria are opsonized with plasma from pwCF. This indicates a novel role for opsonization in neutrophil killing of M. avium and a deficiency in complement opsonization as a mechanism of impaired M. avium killing in CF. IMPORTANCE Mycobacterium avium is a member of a group of bacterial species termed nontuberculous mycobacteria (NTM) that cause lung disease in certain populations, including persons with cystic fibrosis (CF). NTM infections are challenging to diagnose and can be even more difficult to treat. This study investigated how the immune system responds to M. avium infection in CF. We found that neutrophils, the most abundant immune cell in the lungs in CF, can effectively kill M. avium in individuals both with and without CF. Another component of the immune response called the complement system is also required for this process. Levels of complement proteins are altered in persons with CF who have a history of NTM compared to those without a history of NTM infection. These results add to our understanding of how the immune system responds to M. avium, which can help pave the way toward better diagnostic and treatment strategies.
| S-EPMC9927418 | biostudies-literature
Project description:This study was conducted to descripe transcriptomic changes of M.tuberculosis during neutrophil infection
2019-11-09 | GSE140156 | GEO
Project description:BackgroundMycobacterium tuberculosis (TB) infection induces systemic inflammation that could impact HIV-1 persistence.SettingHIV-1-seropositive individuals either with or without pulmonary TB disease were recruited in Kampala, Uganda.MethodsPlasma cytokines, HIV-1 DNA, and cell-associated (ca)-RNA were compared among those coinfected with TB (cases) to those without TB (controls). TB-coinfected cases and controls were compared at presentation (n = 15 and n = 16, respectively) and at around 6 months after HIV-1 treatment initiation among those who had achieved virologic suppression (n = 6 and n = 8, respectively). At follow-up, the TB-coinfected cases had also finished TB treatment.ResultsBefore treatment, the TB-coinfected cases as compared to the controls had higher levels of soluble(s)-CD163 (P = 0.0002) and interleukin-6 (P = 0.006) but lower levels of macrophage chemoattractant protein-1 (P = 0.04). After treatment, the TB-coinfected cases as compared to controls still had higher plasma s-CD163 levels (P = 0007). Controls as compared to the coinfected cases had higher ca-RNA per DNA template both at baseline (P = 0.03) and at follow-up (P = 0.07). Levels of ca-RNA per DNA copy at follow-up showed a negative correlation with baseline plasma s-CD163 (P = 0.008) and interleukin-6 (P = 0.05) levels.ConclusionsTB disease is associated with inflammation and decreased HIV-1 RNA expression relative to the number of infected cells, both before and after viral suppression. Infections present before antiretroviral initiation impact HIV-1 latency.
| S-EPMC6506856 | biostudies-literature
Project description:Mycobacterium tuberculosis is a highly successful human pathogen that primarily resides in host phagocytes, such as macrophages and dendritic cells (DCs), and interferes with their functions. Although multiple strategies used by M. tuberculosis to modulate macrophage responses have been discovered, interactions between M. tuberculosis and DCs are less well understood. DCs are the primary APCs of the immune system and play a central role in linking innate and adaptive immune responses to microbial pathogens. In this study, we show that M. tuberculosis impairs DC cytokine secretion, maturation, and Ag presentation through the cell envelope-associated serine hydrolase, Hip1. Compared to wild-type, a hip1 mutant strain of M. tuberculosis induced enhanced levels of the key Th1-inducing cytokine IL-12, as well as other proinflammatory cytokines (IL-23, IL-6, TNF-?, IL-1?, and IL-18) in DCs via MyD88- and TLR2/9-dependent pathways, indicating that Hip1 restricts optimal DC inflammatory responses. Infection with the hip1 mutant also induced higher levels of MHC class II and costimulatory molecules CD40 and CD86, indicating that M. tuberculosis impairs DC maturation through Hip1. Further, we show that M. tuberculosis promotes suboptimal Ag presentation, as DCs infected with the hip1 mutant showed increased capacity to present Ag to OT-II- and early secreted antigenic target 6-specific transgenic CD4 T cells and enhanced Th1 and Th17 polarization. Overall, these data show that M. tuberculosis impairs DC functions and modulates the nature of Ag-specific T cell responses, with important implications for vaccination strategies.
| S-EPMC3995873 | biostudies-literature
Project description:Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.
| S-EPMC4084802 | biostudies-literature
Project description:BackgroundThe urine lipoarabinomannan (LAM) lateral flow assay is a point-of-care test to diagnose HIV-associated tuberculosis (TB). We assessed the performance of urine LAM in HIV-positive patients presenting to the emergency center and evaluated the interobserver agreement between emergency center physicians and laboratory technologists.SettingA cross-sectional diagnostic study was performed at the emergency center of a district hospital in a high HIV-prevalence community in South Africa.MethodsConsecutive HIV-positive adults presenting with ≥1 WHO TB symptom were enrolled over a 16-month period. A urine LAM test was performed at point-of-care by an emergency physician and interpreted independently by 2 physicians. A second test was performed in the laboratory and interpreted independently by 2 laboratory technologists. The reference standard was a positive TB culture or Xpert MTB/RIF test on sputum or appropriate extrapulmonary samples. We compared diagnostic accuracy and reproducibility of urine LAM between point-of-care readers and laboratory readers.ResultsOne thousand three hundred eighty-eight samples (median, 3 samples/participant) were sent for TB microbiology tests in 411 participants; 170 had confirmed TB (41.4%). Point-of-care and laboratory-performed urine LAM had similar sensitivity (41.8% vs 42.0%, P = 1.0) and specificity (90.5% vs 87.5%, P = 0.23). Moderate agreement was found between point-of-care and laboratory testing (κ = 0.62), but there was strong agreement between point-of-care readers (κ = 0.95) and between laboratory readers (κ = 0.94). Positive percent agreement between point-of-care and laboratory readers was 68% and negative percent agreement 92%.ConclusionThere is no diagnostic accuracy advantage in laboratory-performed versus point-of-care-performed urine LAM tests in emergency care centers in high-burden settings.
| S-EPMC6522362 | biostudies-literature
Project description:BackgroundGranulomas caused by Mycobacterium Tuberculosis have been observed at autopsy in the heart, pre-dominantly in the myocardium and endocardium, but rarely involving the coronary vessels and valvular structures. Mycobacterium tuberculosis valvular endocarditis is extremely rare, with most reports coming from autopsy series.Case presentationWe report the case of a 17 year old immunocompetent girl who presented with history of fever, malaise, foot gangrene and a left sided hemiparesis. On investigation she was found to have infective endocarditis involving the aortic, mitral and tricuspid valves. She had developed a right middle cerebral artery stroke. She underwent dual valve replacement and tricuspid repair. The vegetations showed granulomatous inflammation but blood cultures and other biological specimen cultures were negative for any organisms. She was started on antituberculous treatment and anticoagulation.ConclusionThis is the first reported case of triple valve endocarditis by Mycobacterium Tuberculosis in an immunocompetent host. Especially important is the fact that the right heart is involved which has been historically described in the setting of intravenous drug abuse.This implies that Tuberculosis should be considered in cases of culture negative endocarditis in endemic areas like Pakistan even in immunocompetent hosts.
| S-EPMC3511257 | biostudies-literature
Project description:We admitted a patient with extensive and rapidly progressing necrotizing fasciitis, pulmonary tuberculosis, cutaneous tuberculosis, and bacterial infections because of late diagnosis and treatment. Early diagnosis is necessary for both cutaneous tuberculosis and necrotizing fasciitis. However, these are rare clinical manifestations and are difficult to detect. Despite surgical and pharmacologic treatment, the patient had poor outcomes. We discussed the next-generation sequencing test for early tuberculosis diagnosis, especially for atypical ones. The modified and typical laboratory risk indicator for necrotizing fasciitis score was used for diagnosing and identifying patients at high risk for necrotizing fasciitis. Subcutaneous effusions and gas accumulations observed through imaging were useful in assessing necrotizing fasciitis progression. Debridement or tuberculosis treatment should be initiated as early as possible in managing patients with both necrotizing fasciitis and cutaneous tuberculosis. Clinicians should be alert in identifying the condition, whether Mycobacteria tuberculosis is the independent cause of necrotizing fasciitis, and treating the condition. The choice of rapid microbial diagnostic tools should be of concern. Debridement or tuberculosis treatment should be initiated as early as possible in managing patients with both necrotizing fasciitis and cutaneous tuberculosis. Multidisciplinary cooperation should be considered.
| S-EPMC10568099 | biostudies-literature